The pyroglutamate hydantoin rearrangement

Article abstract of DOI:10.1002/ejoc.200600051

When a mixture of a pyroglutamate and an isocyanate in THF is treated with NaH, a ring transformation occurs leading to functionalised hydantoins. The novel reaction involves a ring-closing ring-opening sequence providing a new and straightforward access

Full text of DOI:10.1002/ejoc.200600051

FULL PAPER
DOI: 10.1002/ejoc.200600051
The Pyroglutamate Hydantoin Rearrangement
Nicolai Dieltiens,[a] Diederica D. Claeys,[a][‡] Viktor V. Zhdankin,[b] Victor N. Nemykin,[b]
Bart Allaert,[c] Francis Verpoort,[c] and Christian V. Stevens*[a]
Keywords: Nitrogen heterocycles / Lactams / Fused-ring systems / Rearrangement / Pyroglutamates / Hydantoins / Ring-
closing metathesis / Isocyanates
When a mixture of a pyroglutamate and an isocyanate in
THF is treated with NaH, a ring transformation occurs lead-
ing to functionalised hydantoins. The novel reaction involves
a ring-closing ring-opening sequence providing a new and
straightforward access to an interesting class of heterocyclic
compounds. Furthermore, starting from pyroglutamates al-
lows the synthesis of highly substituted hydantoins under
very mild conditions. This ring transformation in combination
with ring-closing metathesis is used in a four-step reaction
sequence for the synthesis of multi-functionalised bicyclic
hydantoin derivatives.
(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2006)
cle.[21–27] In this article we wish to report on the single-step
transformation of pyroglutamates to hydantoins, and the
use of this ring transformation in combination with ring-
closing metathesis for the synthesis of heavily substituted
bicyclic hydantoin derivatives.
Introduction
Pyroglutamates and their transformations have received
a lot of attention over the years because of their importance
in several domains. Pyroglutamic acid (1) (Figure 1) is a
very useful and versatile starting material for the synthesis
of both natural and unnatural products.[1] Intensive study
of glutamate analogues resulted in specific inhibitors of dif-
ferent receptor types of the mammalian central nervous sys-
tem.[2,3] It has also been used for the synthesis of pyrroli-
dine alkaloids,[4,5] kainoids,[6] (–)-bulgecinine,[7] (–)-domoic
acid,[8] enantiomerically pure glycine and proline deriva-
tives,[9] a wide variety of non-proteinogenic amino acids,[10]
etc. During the last decade, hydantoins (or imidazolidine-
2,4-diones, 2) have been extensively studied and are re-
ported to possess a wide range of biological activities.
Phenetoin (5,5-diphenylhydantoin, 3) for example was al-
ready synthesised in 1908[11] and is now still the drug of
choice for the treatment of certain types of epileptic sei-
zures.[12] They have not only proven useful in human medi-
cine (antiarrhytmic,[13] anticonvulsant,[14,15] antitumour,[16]
antidiabetic,[17,18] antimuscarinic,[19] ... activity), but also in
the agrochemical sector (herbicidal and fungicidal ac-
tivity).[20] In recent years many new synthetic approaches
have been developed towards this interesting heterocy-
Figure 1. Pyroglutamic acid (1), the hydantoin nucleus (2) and
phenetoin (3).
Results and Discussion
The Pyroglutamate Hydantoin Rearrangement
During our research on pyroglutamates for the develop-
ment of agrochemicals and pharmaceutically interesting
azaheterocyclic skeletons, we found that when the sodium
salt of an alkyl pyroglutamate 4 is treated with 1 equivalent
of an isocyanate, reaction occurs both on the N atom and
on the C2 atom resulting in a complex mixture of different
compounds. However, when a mixture of 4 with an isocya-
[a] Research group Synbioc, Department of Organic Chemistry, nate is treated with NaH in diethyl ether, a precipitate is
Faculty of Bioscience Engineering, Ghent University,
formed during the reaction, which after workup proved to
Coupure links 653, 9000 Ghent, Belgium
be the sodium salt of the expected carbamoyllactam 5 in
high purity (Scheme 1). On the other hand, if the reaction
is performed in THF no precipitate is formed, and after
workup a compound was isolated which gave a different
Fax: +32-9-2646243
E-mail: chris.stevens@ugent.be
[b] Department of Chemistry, University of Minnesota Duluth,
Duluth, Minnesota 55812, USA
[c] Division of Organometallics and Catalysis, Department of In-
organic and Physical Chemistry, Ghent University,
Krijgslaan 281 (S-3), 9000 Ghent, Belgium
[‡] D. D. C. is aspirant of the FWO (Fund for Scientific Research
Flanders)
1
but very similar H NMR spectrum. It was assumed that
intermediate 5 (Scheme 1), which is apparently soluble in
THF, reacts intramolecularly by a nucleophilic attack on
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C. V. Stevens et al.
FULL PAPER
Scheme 1.
the carbonyl of the ester function followed by expulsion of
an alkoxide anion resulting in the formation of the bicyclic
intermediate 6. The alkoxide anion in turn can open this
bicyclic intermediate with formation of the anions 7 and 8.
These anions are in equilibrium with each other, causing
racemisation of the chiral centre (this was proven by
quenching the reaction with D2O). Upon work up this re-
sulted in the hydantoin derivatives 9 as a 1:1 mixture of its
enantiomers.
Table 1. Synthesis of hydantoin derivatives 9 by ring transformation
of pyroglutamates 4.
In contrast, the isolated carbamoyllactams 10 (R1 = Et,
R2 = Bn) and 11 (R1 = Et, R2 = Ph)[28] are still optically
active. Because we now had both the carbamoyllactam 10
and the hydantoin derivative 9e in hand, it was easy to com-
pare all the spectroscopic data. From their structures it is
1
obvious that they would have very similar H NMR and
13C NMR spectra, hence no conclusions could be made
judging these spectra alone. The decisive proof was given
by comparing both COSY (Correlated Spectroscopy) and
HMBC (Heteronuclear Multiple Bound Correlation) cou-
pled spectra (Figure 2). In the case of 10, there is a coupling
in the COSY spectrum between the proton on the N atom
and the two protons of the benzyl group, the proton on
nitrogen appears as an incompletely resolved triplet. In the
case of 9e, however, the proton on the N atom couples with
the proton next to the carbonyl and not with the protons
of the benzyl group, proving that the benzyl group is at-
tached to a tertiary nitrogen. Furthermore, in the HMBC
spectrum, the protons of the benzyl group of 10 only couple
to the urea carbonyl (easily distinguishable from both other
carbonyl groups), whereas in the case of 9e they couple to
both the urea and the lactam carbonyl.
Figure 2. Characteristic COSY and HMBC couplings of 10 and 9e.
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The Pyroglutamate Hydantoin Rearrangement
FULL PAPER
Since it was established that the hydantoin was synthe- formed caused by fragmentation of the ester. This kind of
sised, the same methodology was performed on other com- fragmentation has been observed before.[33] Therefore, all
binations of pyroglutamate esters and isocyanates (Table 1). following reactions were carried out on the ethyl ester.
We were pleased to find that different esters underwent
the same reaction, although, in some cases, traces of car-
bamoyllactam could be observed due to the poor solubility
of this intermediate in THF. This is probably the reason
why the benzyl ester formed a hydantoin with phenyl iso-
thiocyanate (Entry 3), whereas the ethyl ester only gave the
thiocarbamoylated pyroglutamate.
Synthesis of Bicyclic Hydantoin Derivatives
Having discovered this ring transformation and estab-
lished its general nature, we wanted to use this reaction as
the key step in the synthesis of more complex hydantoins.
Our goal was the synthesis of a new series of more con-
Scheme 3. Reagents and conditions: 4 equiv. electrophile, 2.1 equiv.
strained bicyclic derivatives 15. These compounds have at-
tracted the attention of a number of research groups due to
their potential biological application and as a template in
organic synthesis.[29,30] Our strategy to synthesise this het-
erocyclic skeleton, started from a pyroglutamate ester 4
(Scheme 2). The first step is functionalisation at the C2 po-
sition, which afforded compound 12. Next carbamoylation
and immediate ring transformation would provide the hy-
dantoin derivatives 13. Subsequent N-alkylation to afford
14 and RCM would provide the envisaged compounds
15.[31] This strategy provides the possibility of varying sub-
stituents at four positions and thus would be ideal to syn-
thesise a library of highly functionalised molecules.
LiHMDS, THF, 30 min at –40 °C, then 2 h at room temp.
The ring transformation was then performed using dif-
ferent isocyanates (Scheme 4). In almost all cases, small
amounts of the carbamoyllactam 16 were formed together
with the desired hydantoins 13 thus requiring purification.
It was observed that bulky R2 substituents (e.g. 12d and
12i) prevent the pyroglutamate from reacting with the isocy-
anate even under more drastic conditions (reflux in DMF).
In these cases only unreacted starting material could be re-
covered. Also compound 12f, with a propyne substituent
at C2, gave a mixture of compounds upon reaction with
isocyanates and was therefore not further used.
Scheme 2. Retrosynthetic analysis of bicyclic hydantoin derivatives
15.
Scheme 4. Reagents and conditions: R3NCO, NaH, THF, room
temp., 16 h.
Although alkylation of pyroglutamates at the C2 posi-
tion has been described before,[32] this method is rather un-
practical with the need for stringent time and temperature
As is the case for the derivatives 9, 2D-spectra confirm
control. It was found that excellent results can be obtained the structure of compounds 13 (Figure 3). An example is
when a mixture of the pyroglutamate and the electrophile shown in Figure 3: In the HMBC spectrum of 13c, the pro-
is treated with 2.1 equivalents of LiHMDS at –40 °C tons of the allyl substituent, of the benzyl group and on the
(Scheme 3). Even when using several equivalents of electro- N atom couple to the same carbon at δ = 175.0 ppm.
phile, no N-alkylation was observed. This methodology
The hydantoins 13 obtained in this fashion proved to be
however, can not be followed if base-sensitive electrophiles rather poor nucleophiles. Treatment with strong bases did
are used (e.g. in case of 12e and 12f). When using the benzyl not lead to alkylation, but resulted in partial decomposition
ester, however, small amounts of benzyl alcohol were of the starting material. The only way to alkylate these com-
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C. V. Stevens et al.
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Table 2. Synthesis of bicyclic hydantoin derivatives using RCM.
Figure 3. Characteristic HMBC couplings of 13c and chemical
shifts of the carbonyl carbon atoms.
pounds at N1 in good yield was to reflux them with 2 equiv-
alents of electrophile and 5 equivalents of finely ground
K2CO3 in acetone for several days (Scheme 5).
Scheme 5. Reagents and conditions: electrophile, K2CO3, acetone,
reflux.
Finally, ring-closing metathesis on substrates 14 provided
the envisaged bicyclic structures 15 in excellent yields
(Table 2). The second-generation Grubbs’ catalyst 16[34] and
Hoveyda–Grubbs’ catalyst 17[35] (Figure 4) provide the pos-
sibility of performing RCM on a variety of substrates with
different substituents on the double bond. Substrates with
a vinylic or allylic chloride (15c, 15e, 15g) or an extra ester
functionality (15f) thus provide the possibility of further
functionalisation.[36]
Figure 5 shows the structure obtained by X-ray analysis
of derivative 15b. As expected, the five-membered cycle is
planar with the typical C=O bonds of 1.21 Å. The observed
torsion angle of 44.05° between the five-membered and the
phenyl rings (C3–N4–C7–C12) confirms the non-coplanar
configuration of these molecular fragments. The annelated
partially saturated six-membered ring (C1–N2–C14–C15–
C16–C17) has the pseudo-envelope conformation in which
all atoms but C1 are in the same plane with the observed
C15–C14–N2–C1 torsion angle of 39.07°. An observed
C15–C16 bond length of 1.371 Å clearly indicates the pres-
ence of the double bond between these atoms formed by
the RCM reaction. The ester fragment adopts a typical zig-
zag conformation with the expected bond lengths. Finally,
we were not able to find any significant intra- and intermo-
lecular interactions in the crystal packing of the compound
15b.
Figure 4. Second-generation Grubbs’ catalyst 16 and Hoveyda-
Grubbs’ catalyst 17.
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The Pyroglutamate Hydantoin Rearrangement
FULL PAPER
matrix least-squares on F2 using Crystals for Windows program.[39]
All of the non-hydrogen atoms were refined anisotropically. Se-
lected data: 15b: C18H20N2O4, M = 328.37, triclinic, space group
¯
P1, a = 8.2050(16), b = 9.5970(19), c = 12.045(2) Å; α = 77.59(3),
3
β = 79.65(3), γ = 67.39(3)°, V = 850.2(4) Å , Z = 2, T = 293 K, µ
= 0.091 mm–1, 4215 reflections measured, 3037 unique (Rint
0.0832); final R1 = 0.051, Rw = 0.129.
=
CCDC-287973 contains the supplementary crystallographic data
for this paper. These data can be obtained free of charge from The
Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/
data_request/cif.
Typical Experimental Procedure for the Alkylation of Pyroglutam-
ates at the 2-Position: The pyroglutamate ester (12 mmol) was dis-
solved in THF (15 mL, freshly distilled from Na metal) and the
alkyl halide (48 mmol) was added. The mixture was cooled to
–40 °C under N2. Over
a period of 30–40 min, LiHMDS
(25.2 mmol, solution in hexane) was added at this temperature. The
mixture was stirred at room temperature for an additional 2 h and
the reaction then quenched by addition of saturated aqueous
NH4Cl until the pH was neutral. The mixture was extracted with
EtOAc, and the organics were dried (MgSO4) and filtered. The
solvent was removed in vacuo.
Figure 5. X-ray structure of bicyclic derivative 15b.[37]
Conclusions
Ethyl 2-Allyl-5-oxopyrrolidine-2-carboxylate (12a): Yield: 1.70 g
In the present study we have described a new ring trans-
formation of pyroglutamates leading to hydantoins in one
step in good to high yields. This rearrangement proceeds
through a ring-closing ring-opening sequence. Furthermore,
the general nature of this rearrangement was proven using
different pyroglutamate esters and isocyanates. The re-
arrangement was used in a reaction sequence in combina-
tion with ring-closing metathesis for the synthesis of multi-
functionalised bicyclic hydantoins, expanding the synthetic
scope and utility of pyroglutamates.
1
(72%). H NMR (270 MHz, CDCl3): δ = 1.29 (t, J = 7.1 Hz, 3 H,
CH2CH3), 2.07–2.17 (m, 1 H, COCH2CHAHB), 2.35–2.51 (m, 4 H,
COCH2CHAHB + CCHAHB), 2.63–2.71 (m, 1 H, CCHAHB), 4.22
(q, J = 7.1 Hz, 2 H, CH2CH3), 5.14–5.21 (m, 2 H, CH=CH2), 5.69
(dddd, J = 6.5 Hz, J = 7.9 Hz, J = 10.9 Hz, J = 16.2 Hz, 1 H,
CH=CH2), 6.35 (br s, 1 H, NH) ppm. 13C NMR (68 MHz, CDCl3):
δ = 14.20 (CH2CH3), 29.88 (COCH2CH2), 30.04 (COCH2), 43.38
(CH2CH=CH2), 61.72 (CH2CH3), 65.35 (Cq), 120.41 (CH=CH2),
131.19 (CH=CH2), 173.19 (NHC=O), 177.25 (C=OO) ppm. MS:
m/z (%) = 198 (100) [M+H+]. IR: ν
= 1711 (br C=O) cm–1.
˜
max
C10H15NO3 (197.23): calcd. C 60.90, H 7.67, N 7.10; found C
60.74, H 7.77, N 7.09.
Experimental Section
Ethyl 5-Oxo-2-(2-chloromethylprop-2-enyl)pyrrolidine-2-carboxylate
(12b): Yield: 1.83 g (62%). M.p. 55.4–56.6 °C. 1H NMR (270 MHz,
CDCl3): δ = 1.31 (t, J = 7.1 Hz, 3 H, CH2CH3), 2.12–2.22 (m, 1
H, COCH2CHAHB), 2.37–2.54 (m, 3 H, COCH2CHAHB), 2.54 (d,
J =14.5 Hz, 1 H, CCHAHB), 2.94 (d, J =14.5 Hz, 1 H, CCHAHB),
4.00 (s, 2 H, CH2Cl), 4.22 (q, J =7.1 Hz, 2 H, CH2CH3), 5.06 (s, 1
H, C=CHAHB), 5.33 (s, 1 H, C=CHAHB), 6.41 (br s, 1 H, NH)
ppm. 13C NMR (68 MHz, CDCl3): δ = 14.11 (CH2CH3), 29.69
(COCH2CH2), 31.23 (COCH2), 41.74 (CCH2), 48.41 (CH2Cl),
61.99 (CH2CH3), 65.07 (Cq), 120.03 (C=CH2), 139.91 (C=CH2),
173.19 (NHC=O), 177.21 (C=OO) ppm. MS: m/z (%) = 246.0/
General Remarks: High-resolution 1H NMR (270 MHz) and 13C
NMR (68 MHz) spectra were run with a Jeol JNM-EX 270 NMR
spectrometer or with a Jeol JNM-EX 300 NMR spectroscopy. Peak
assignments were obtained with the aid of DEPT, 2D-HETCOR,
2D-COSY spectra. The compounds were diluted in deuterated sol-
vents and the used solvent is indicated for each compound. Low-
resolution mass spectra were recorded with an Agilent 1100 Series
VS. (ES = 4000 V) mass spectrometer. IR spectra were obtained
with a Perkin–Elmer Spectrum One infrared spectrometer. For li-
quid samples the spectra were collected by preparing a thin film
of compound between two sodium chloride plates. The crystalline
compounds were mixed with potassium bromide and pressed until
a transparent potassium bromide plate was obtained. Melting
points of crystalline compounds were measured with a Büchi 540
apparatus and are uncorrected. The elemental analysis was per-
formed with a Perkin–Elmer 2400 Elemental Analyzer. The purifi-
cation of reaction mixtures was performed by flash chromatog-
raphy using a glass column with silica gel (Across, particle size
0.035–0.070 mm, pore diameter ca. 6 nm). Single crystals of com-
pound 15b as colourless plates were grown by slow evapouration
of its CDCl3 solution. The X-ray data were collected with a Rigaku
AFC-7R diffractometer using graphite-monochromated Mo-Kα ra-
diation (λ = 0.71073 Å) at 293 K. Psi-scan absorption corrections
were applied to the data using TeXsan 10.3b program.[38] The struc-
tures were solved by direct methods (SIR-92) and refined by full-
248.0 (100) [M+H+]. IR: ν
= 1707 (C=O), 1741 (C=O) cm–1.
˜
max
C11H16ClNO3 (245.70): calcd. C 53.77, H 6.56, N 5.70; found C
53.73, H 6.43, N 5.66.
Ethyl 2-(2-Methylprop-2-enyl)-5-oxopyrrolidine-2-carboxylate (12c):
1
Yield: 2.13 g (84%). H NMR (300 MHz, CDCl3): δ = 1.30 (t, J =
7.2 Hz, 3 H, CH3), 1.72 (s, 3 H, CH3), 2.09–2.19 (m, 1 H, CO-
CHAHB), 2.35–2.52 (m, 3 H, COCHAHBCH2), 2.37 (dd, J = 2.6
Hz, J = 13.7 Hz, 1 H, CCHAHBC), 2.69 (d, J = 13.7 Hz, 1 H,
CCHAHBC), 4.21 (q, J = 7.2 Hz, 2 H, CHAHBCH3), 4.76 (s, 1 H,
C=CHAHB), 4.92 (s, 1 H, C=CHAHB), 6.27 (br s, 1 H, NH) ppm.
13C NMR (75 MHz, CDCl3): δ = 14.19 (CH2CH3), 23.57 (CH3),
29.69 (COCH2CH2), 31.66 (COCH2), 47.11 (CCH2C), 61.88
(CH2CH3), 65.02 (Cq), 116.11 (C=CH2), 139.96 (CH3C=CH2),
173.52 (HNC=O), 176.72 (C=OO) ppm. IR: ν
= 1647 (C=C),
˜
max
1706 (C=O), 1735 (C=O), 3220 (br NH) cm–1. MS: m/z (%) = 212.8
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C. V. Stevens et al.
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(100) [M+H+]. C11H17NO3 (211.26): calcd. C 62.54, H 8.11, N
6.63; found C 62.36, H 8.13, N 6.59.
Ethyl 2-(2-Chloroprop-2-enyl)-5-oxopyrrolidine-2-carboxylate (12e):
Yield: 1.28 g (46%). M.p. 90.3° C. H NMR (300 MHz, CDCl3): δ
1
= 1.30 (t, J = 7.2 Hz, 3 H, CH3), 2.13–2.23 (m, 1 H, COCHAHB),
2.36–2.43 (m, 2 H, COCH2CH2), 2.46–2.56 (m, 1 H, COCHAHB),
2.71 (d, J = 14.3 Hz, 1 H, CCHAHBC), 3.05 (d, J = 14.3 Hz, 1 H,
CCHAHBC), 4.22 (q, J = 7.2 Hz, 1 H, CHAHBCH3), 4.23 (q, J =
7.2 Hz, 1 H, CHAHBCH3), 5.25 (t, J = 0.7 Hz, 1 H, C=CHAHB),
5.35 (d, J = 1.4 Hz, 1 H, C=CHAHB), 6.29 (br s, 1 H, NH) ppm.
Ethyl 5-Oxo-2-(2-phenylprop-2-enyl)pyrrolidine-2-carboxylate (12d):
Yield: 2.30 g (70%). M.p. 73.4–74.4 °C. 1H NMR (300 MHz,
CDCl3): δ = 1.12 (t, J = 7.2 Hz, 3 H, CH3), 2.05–2.17 (m, 1 H,
COCHAHB), 2.23–2.36 (m, 2 H, COCH2CH2), 2.23–2.49 (m, 1 H,
COCHAHB), 2.86 (d, J = 13.6 Hz, 1 H, CCHAHBC), 3.21 (d, J =
12.1 Hz, 1 H, CCHAHBC), 3.75 (q, J = 7.2 Hz, 1 H, CHAHBCH3),
3.76 (q, J = 7.2 Hz, 1 H, CHAHBCH3), 5.15 (s, 1 H, C=CHAHB),
5.33 (d, J = 1.4 Hz, 1 H, C=CHAHB), 5.98 (br s, 1 H, NH), 7.29–
7.35 (m, 5 H, Ph) ppm. 13C NMR (75 MHz, CDCl3): δ = 13.97
(CH3), 29.60 (COCH2CH2), 31.49 (COCH2), 45.05 (CCH2C), 61.69
(CH2CH3), 65.46 (Cq), 118.52 (C=CH2), 126.69 (CHar), 128.15
(CHar), 128.55 (CHar), 140.54 (C=CH2), 143.68 (Cq,ar), 172.87
13C NMR (75 MHz, CDCl3):
δ
=
14.18 (CH3), 29.31
(COCH2CH2), 31.58 (COCH2), 48.13 (CCH2C), 62.23 (CH2CH3),
64.72 (Cq), 117.85 (C=CH2), 136.20 (CCl=CH2), 172.51 (HNC=O),
176.52 (C=OO) ppm. IR: ν
= 1636 (.C=C), 1715 (C=O), 1741
˜
max
(C=O), 3195 (br NH) cm–1. MS: m/z (%) = 232.7/234.7 (100)
[M+H+]. C10H14ClNO3 (231.68): calcd. C 51.84, H 6.09, N 6.05;
found C 51.44, H 6.26, N 6.10.
(HNC=O), 176.42 (C=OO) ppm. IR: ν
= 1728 (C=O), 1744
˜
max
(C=O), 3203 (br NH) cm–1. MS: m/z (%) = 274.3 (100) [M+H+].
Chromatography [Hex/EtOAc (4:6)]: Rf = 0.21. C16H19NO3 (273.33):
calcd. C 70.31, H 7.01, N 5.12; found C 70.10, H 7.04, N 5.04.
Ethyl 5-Oxo-2-prop-2-ynylpyrrolidine-2-carboxylate (12f): Yield:
0.47 g (20%). 1H NMR (300 MHz, CDCl3): δ = 1.31 (t, J = 7.2
Hz, 3 H, CH3), 2.08 (t, J = 2.2 Hz, 1 H, CH), 2.12–2.52 (m, 4 H,
COCH2CH2), 2.61 (dd, J = 14.3 Hz, J = 2.2 Hz, 1 H, CCHAHBC),
2.82 (dd, J = 14.3 Hz, J = 2.2 Hz, 1 H, CCHAHBC), 4.25 (q, J =
7.2 Hz, 2 H, CH2CH3), 5.25 (t, J = 0.7 Hz, 1 H, C=CHAHB), 7.01
(br s, 1 H, NH) ppm. 13C NMR (75 MHz, CDCl3): δ = 14.13
(CH3), 29.09 (COCH2CH2), 29.79 (CCH2C + COCH2), 62.15
(CH2CH3), 64.67 (Cq), 72.11 (CH), 78.21 (C), 172.33 (HNC=O),
Benzyl 2-Allyl-5-oxopyrrolidine-2-carboxylate (12g): Yield: 2.58 g
(83%). 1H NMR (270 MHz, CDCl3): δ = 2.09–2.16 (m, 1 H,
COCH2CHAHB), 2.33–2.47 (m, 4 H, COCH2CHAHB + CCHAHB),
2.66 (dd, J = 6.4 Hz, J = 13.7 Hz, 1 H, CCHAHB), 5.09–5.16 (m,
2 H, CH=CH2), 5.17 (s, 2 H, CH2Ph), 5.61 (dddd, J = 6.6 Hz, J =
8.3 Hz, J = 10.4 Hz, J = 16.7 Hz, 1 H, CH=CH2), 7.33–7.37 (m,
177.36 (C=OO) ppm. IR: ν
= 1705 (br C=O), 2120 (alkyne),
˜
max
5
H, Ph) ppm. 13C NMR (68 MHz, CDCl3):
δ = 29.72
3283 (br NH) cm–1. MS: m/z (%) = 391.7, (100) [2M+H+].
Chromatography [Hex/EtOAc (2:8)]: Rf = 0.3. C10H13NO3 (195.22):
calcd. C 61.53, H 6.71, N 7.18; found C 61.73, H 6.77, N 7.13.
(COCH2CH2), 30.17 (COCH2), 43.45 (CCH2), 65.28 (Cq), 67.53
(CH2Ph), 120.81 (CH=CH2), 128.41 (CHar), 128.71 (CHar), 130.78
(CH=CH2), 135.09 (Cq,ar), 172.85 (NHC=O), 176.91 (C=OO) ppm.
MS: m/z (%) = 260 (100) [M+H+]. IR: ν
= 1703 (C=O), 1736
Ethyl 2-[2-(Morpholin-4-ylmethyl)prop-2-enyl]-5-oxopyrrolidine-2-
carboxylate (12i): Ethyl 5-oxo-2-(2-chloromethylprop-2-enyl)pyr-
rolidine-2-carboxylate (4 mmol) was dissolved in THF (20 mL,
freshly distilled from Na metal). Morpholine (10 mmol) was added
and the mixture was refluxed until TLC analysis showed that all
starting material was consumed. Then the mixture was cooled and
aqueous NaHCO3 (15 mL) was added. The mixture was extracted
with EtOAc, and the organics were dried (MgSO4) and filtered.
The solvent was removed in vacuo, and the residue was purified by
flash chromatography. Yield: 0.71 g (60%). 1H NMR (300 MHz,
CDCl3): δ = 1.27 (t, J = 7.2 Hz, 3 H, CH3), 1.98–2.08 (m, 1 H,
COCHAHB), 2.23 (d, J = 13.5 Hz, 1 H, CCHAHBC), 2.31–2.56 (m,
7 H, COCHAHBCH2 + CH2NCH2), 2.75 (d, J = 12.1 Hz, 1 H,
NCHAHBC), 2.94 (d, J = 12.1 Hz, 1 H, NCHAHBC), 2.98 (d, J =
13.5 Hz, 1 H, CCHAHBC), 3.68–3.87 (m, 4 H, CH2OCH2), 4.16
(q, J = 7.2 Hz, 2 H, CH2CH3), 5.01 (s, 1 H, C=CHAHB), 5.07 (s,
1 H, C=CHAHB), 9.19 (br s, 1 H, NH) ppm. 13C NMR (75 MHz,
CDCl3): δ = 14.35 (CH3), 30.26 (COCH2CH2), 32.76 (COCH2),
47.54 (CCH2C), 53.31 (CH2NCH2), 61.49 (CH2CH3), 65.37
(CCH2N), 65.94 (Cq), 66.73 (CH2OCH2), 122.43 (C=CH2), 139.22
˜
max
(C=O) cm–1. Chromatography [Hex/EtOAc (25:75)]: Rf = 0.31.
C15H17NO3 (259.30): calcd. C 69.48, H 6.61, N 5.40; found C
69.13, H 6.52, N 5.37.
Benzyl 5-Oxo-2-(2-chloromethylprop-2-enyl)pyrrolidine-2-carboxyl-
ate (12h): Yield: 1.48 g (40%). M.p. 47.3–50.3 °C.1H NMR
(270 MHz, CDCl3): δ = 2.17–2.24 (m, 1 H, COCH2CHAHB), 2.37–
2.50 (m, 3 H, COCH2CHAHB), 2.57 (d, J =14.5 Hz, 1 H,
CCHAHB), 2.96 (d, J =14.5 Hz, 1 H, CCHAHB), 3.96 (s, 2 H,
CH2Cl), 5.02 (s, 1 H, C=CHAHB), 5.20 (d, J =12.0 Hz, 1 H,
CHAHBPh), 5.23 (d, J =12.0 Hz, 1 H, CHAHBPh), 5.30 (s, 1 H,
C=CHAHB), 7.40 (s, 5 H, Ph) ppm. 13C NMR (68 MHz, CDCl3):
δ = 29.61 (COCH2CH2), 31.25 (COCH2), 41.71 (CCH2), 48.37
(CH2Cl), 65.14 (Cq), 67.65 (CH2Ph), 120.09 (C=CH2), 128.52
(CHar), 128.68 (CHar), 134.89 (Cq,ar), 139.67 (C=CH2), 172.97
(NHC=O), 177.18 (C=OO) ppm. MS: m/z (%) = 308.0/310.0 (100)
[M+H+], 257 (7), 91 (7) [Bn+]. IR: νmax = 1701 (C=O), 1735 (C=O)
˜
cm–1. Chromatography [Hex/EtOAc (25:75)]: Rf
=
0.45.
C16H18ClNO3 (307.77): calcd. C 62.44, H 5.89, N 4.55; found C
62.28, H 5.78, N 4.47.
(C=CH ), 173.71 (HNC=O), 176.77 (C=OO) ppm. IR: νmax = 1705
˜
2
(C=O), 1734 (C=O), 3270 (br NH) cm–1. MS: m/z (%) = 297.8 (100)
[M+H+]. Chromatography: First 100% EtOAc until Rf = 0.27 then
strip with CH2Cl2 + 5% MeOH. C15H24N2O4 (296.36): calcd. C
60.79, H 8.16, N 9.45; found C 60.46, H 8.16, N 9.39.
Typical Experimental Procedure for the Alkylation of Pyroglutam-
ates at the 2-Position with Base Sensitive Electrophiles: The pyroglut-
amate ester (12 mmol) was dissolved in THF (15 mL, freshly dis-
tilled from Na metal) and the solution was cooled to –40 °C under
N2. LiHMDS (25.2 mmol, solution in hexane) was added at this
temperature and the mixture was stirred for 20 min followed by
addition of the alkyl halide (48 mmol, dissolved in 5 mL of dry
THF). The mixture was stirred at room temperature for an ad-
ditional 2 h and the reaction then quenched by addition of satu-
rated aqueous NH4Cl until the pH was neutral. The mixture was
extracted with EtOAc, and the organics were dried (MgSO4) and
filtered. The solvent was removed in vacuo, and the residue was
purified by flash chromatography (silica gel; hexane/EtOAc).
Typical Experimental Procedure for the Hydantoin Formation from
Pyroglutamates: The pyroglutamate ester (5 mmol) was dissolved
in THF (40 mL, freshly distilled from Na metal) and the isocyanate
(5.5 mmol) was added followed by NaH (5.5 mmol, washed with
hexanes). The mixture was stirred at room temperature for 16 h.
The reaction was quenched by addition of saturated aqueous
NH4Cl until the pH was neutral. Then the mixture was extracted
with EtOAc, and the organics were dried (MgSO4) and filtered.
The solvent was removed in vacuo, and the residue was purified by
2654
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© 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2006, 2649–2660

The Pyroglutamate Hydantoin Rearrangement
FULL PAPER
recrystallisation in case of solids or by flash chromatography (silica
gel; hexane/EtOAc) in case of liquids.
(s, 2 H, CH2Ph), 6.29 (br s, 1 H, NH), 7.25–7.39 (m, 5 H, Ph) ppm.
13C NMR (75 MHz, CDCl3): δ = 14.12 (CH3), 26.84 (CH2), 29.51
(CH2), 42.14 (CH2N), 56.35 (CH), 60.86 (OCH2), 127.89 (CHarom),
128.39 (CHarom), 128.65 (CHarom), 135.96 (Cq. arom), 157.43
(NC=ON), 172.65 (C=O), 173.49 (C=O) ppm. MS (ES, Neg):
Benzyl 3-(2,5-Dioxo-1-phenyl-imidazolidin-4-yl)propanoate (9a):
Yield: 0.95 g (56%). M.p. 144,5–145,4 °C. 1H NMR (300 MHz,
CDCl3): δ = 2.10–2.22 (m, 1 H, CHCHAHB), 2.27–2.38 (m, 1 H,
CHCHAHB), 2.59 (t, J = 7.1 Hz, 2 H, CH2CO), 4.25 (br t, J = 5.6
Hz, 1 H, CHCO), 5.13 (s, 2 H, CH2Ph), 6.36 (br s, 1 H, NH), 7.33–
7.48 (m, 10 H, 2×Ph) ppm. 13C NMR (75 MHz, CDCl3): δ = 27.43
(CH2), 30.18 (CH2), 56.68 (CH), 67.34 (OCH2), 126.59 (CHarom),
128.79 (CHarom), 128.85 (CHarom), 128.93 (CHarom), 129.11
(CHarom), 129.57 (CHarom), 131.75 (Cq. arom) 135.86 (Cq. arom),
156.69 (NC=ON), 172.83 (C=O), 172.99 (C=O) ppm. MS (ES,
m/z (%) = 289.2 (100) [M – H+]. IR (KBr): ν
= 1708 (C=O),
˜
max
1732 (C=O), 1778 (C=O), 3448 (br NH) cm–1. C15H18N2O4
(290.31): calcd. C 62.02, H 6.25, N 9.65; found C 61.80, H 6.19, N
9.72.
Ethyl 3-[1-(2-Chloro-ethyl)-2,5-dioxo-imidazolidin-4-yl]propanoate
(9f): Yield: 1.06 g (81%). 1H NMR (300 MHz, CDCl3): δ = 1.27 (t,
J = 7.2 Hz, 3 H, CH3), 2.01–2.13 (m, 1 H, CHCHAHB), 2.18–2.30
(m, 1 H, CHCHAHB), 2.49 (t, J = 7.4 Hz, 2 H, COCH2), 3.75 (t,
J = 6.1 Hz, 2 H, CH2Cl), 3.84–3.89 (m, 2 H, NCH2), 4.14 (q, J =
7.2 Hz, 2 H, CH2CH3), 4.20 (t, J = 6.1 Hz, 1 H, CH), 7.18 (br s,
1 H, NH) ppm. 13C NMR (75 MHz, CDCl3): δ = 14.37 (CH3),
26.99 (CH2), 29.58 (CH2), 40.17 (CH2N of CH2Cl), 40.73 (CH2N
of CH2Cl), 56.54 (CH), 61.14 (OCH2), 157.42 (NC=ON), 172.93
(C=O), 173.91 (C=O) ppm. MS (ES, Neg): m/z (%) = 261.2/263.2
Neg): m/z (%) = 337.2 (100) [M – H+]. IR (KBr): ν
= 1699
˜
max
(C=O), 1715 (C=O), 1781 (C=O), 3256 (br NH) cm–1. C19H18N2O4
(338.36): calcd. C 67.36, H 5.36, N 8.28; found C 67.03, H 5.43, N
8.27.
Benzyl 3-[1-(2-Chloro-ethyl)-2,5-dioxo-imidazolidin-4-yl]propanoate
1
(9b): Yield: 0.81 g (50%). H NMR (300 MHz, CDCl3): δ = 1.99–
2.11 (m, 1 H, CHCHAHB), 2.14–2.28 (m, 1 H, CHCHAHB), 2.52
(t, J = 7.4 Hz, 2 H, CH2CO), 3.68 (t, J = 5.9 Hz, 2 H, CH2Cl),
3.77–3.82 (m, 2 H, NCH2), 4.13 (br t, J = 6.1 Hz, 1 H, CH), 5.10
(s, 2 H, CH2Ph), 7.12 (br s, 1 H, NH), 7.27–7.38 (m, 5 H, Ph) ppm.
13C NMR (75 MHz, CDCl3): δ = 26.92 (CH2), 29.54 (CH2), 40.13
(CH2N or CH2Cl), 40.74 (CH2N or CH2Cl), 56.44 (CH), 66.90
(OCH2), 128.44 (CHarom), 128.59 (CHarom), 128.83 (CHarom),
135.77 (Cq. arom), 157.44 (NC=ON), 172.67 (C=O), 173.80 (C=O)
ppm. MS (ES, Neg): m/z (%) = 323.3/325.2 (100) [M – H+]. IR
(100) [M – H+]. IR (NaCl): νmax = 1714 (C=O), 1778 (C=O) cm–1.
˜
C10H15ClN2O4 (262.69): calcd. C 45.72, H 5.76, N 10.66; found C
45.70, H 5.71, N 10.63.
Ethyl 3-(1-Allyl-2,5-dioxo-imidazolidin-4-yl)propanoate (9g): Yield:
0.57 g (48%). 1H NMR (300 MHz, CDCl3): δ = 1.26 (t, J = 6.9
Hz, 3 H, CH3), 1.99–2.10 (m, 1 H, CHCHAHB), 2.17–2.28 (m, 1
H, CHCHAHB), 2.48 (t, J = 7.4 Hz, 2 H, COCH2), 4.13 (q, J =
6.9 Hz, 2 H, CH2CH3), 4.11 (d, J = 13.9 Hz, 1 H, NCHAHB), 4.17
(d, J = 13.9 Hz, 1 H, NCHAHB), 4.09–4.19 (m, 1 H, CH), 5.17–
5.24 (m, 2 H, HC=CH2), 5.76–5.88 (m, 1 H, HC=CH2), 7.25 (br s,
1 H, NH) ppm. 13C NMR (75 MHz, CDCl3): δ = 14.31 (CH3),
27.05 (CH2), 29.60 (CH2), 40.41 (NCH2), 56.48 (CH), 61.02
(OCH2), 117.94 (HC=CH2), 131.34 (HC=CH2), 157.65 (NC=ON),
172.81 (C=O), 173.70 (C=O) ppm. MS (ES, Neg): m/z (%) = 239.3
(KBr): ν
= 1714 (br, C=O), 1777 (C=O), 3320 (NH) cm–1.
˜
max
C15H17ClN2O4 (324.76): calcd. C 55.48, H 5.28, N 8.63; found C
55.45, H 5.36, N 8.62.
Benzyl
3-(5-Oxo-1-phenyl-2-thioxo-imidazolidin-4-yl)propanoate
(9c): Yield: 0.74 g (42%). M.p. 157 °C. 1H NMR (300 MHz,
CDCl3): δ = 2.13–2.26 (m, 1 H, CHCHAHB), 2.33–2.44 (m, 1 H,
CHCHAHB), 2.58–2.65 (m, 2 H, CH2CO), 4.35 (dd, J = 5.1 Hz
and J = 6.5 Hz, 1 H, CH), 5.16 (s, 2 H, CH2Ph), 7.28–7.53 (m, 10
H, 2×Ph), 7.66 (br s, 1 H, NH) ppm. 13C NMR (75 MHz, CDCl3):
δ = 26.61 (CH2), 29.85 (CH2), 59.00 (CH), 67.10 (OCH2), 128.25
(CHarom.), 128.50 (CHarom.), 128.56 (CHarom.), 128.69 (CHarom.),
129.18 (CHarom.), 129.32 (CHarom.), 132.54 (Cq. arom.), 135.29
(Cq. arom.), 172.69 (C=O) 173.20 (C=O), 183.71 (C=S) ppm. MS
(100) [M – H+]. IR (KBr): νmax = 1646 (C=C), 1719 (br C=O), 1775
˜
(C=O), 3316 (NH) cm–1. C11H16N2O4 (240.26): calcd. C 54.99, H
6.71, N 11.66; found C 54.63, H 6.73, N 11.63.
Methyl 3-(2,5-Dioxo-1-phenyl-imidazolidin-4-yl)propanoate (9h):
Yield: 1.06 g (81%). M.p. 103–104 °C. 1H NMR (300 MHz,
CDCl3): δ = 1.85–2.22 (m, 1 H, CHCHAHB), 2.25–2.39 (m, 1 H,
CHCHAHB), 2.52–2.58 (m, 2 H, CH2CO), 3.70 and 3.71 (2×s, 3
H, CH3), 4.23–4.28 (m, 1 H, CH), 6.45–6.71 (1 H, br s, NH), 7.36–
7.50 (5 H, m, Ph) ppm. 13C NMR (75 MHz, CDCl3): δ = 27.35
(CH2), 29.66 (CH2), 52.41 (OCH3), 56.54 (CH), 126.59 (CHarom),
128.75 (CHarom), 129.53 (CHarom), 131.74 (Cq. arom), 157.04
(NC=ON), 172.98 (C=O), 173.48 (C=O) ppm. MS (ES, Pos):
(ES, Neg): m/z (%) = 353.2 (100) [M – H+]. IR (KBr): νmax = 1697
˜
(C=S), 1719 (C=O), 1750 (C=O), 3233 (NH) cm–1. C19H18N2O3S
(354.42): calcd. C 64.39, H 5.12, N 7.90; found C 64.15, H 5.30, N
7.82.
Ethyl 3-(2,5-Dioxo-1-phenyl-imidazolidin-4-yl)propanoate (9d):
m/z (%) = 263.3 (100) [M+H+]. IR (KBr): ν
= 1707 (C=O),
1
˜
Yield: 1.23 g (89%). M.p. 84–85 °C. H NMR (300 MHz, CDCl3):
max
1725 (C=O), 1775 (C=O), 3233 (NH) cm–1. C13H14N2O4 (262.26):
δ = 1.26 (t, J = 7.2 Hz, 3 H, CH3), 2.08–2.20 (m, 1 H, CHCHAHB),
2.26–2.37 (m, 1 H, CHCHAHB), 2.53 (t, J = 6.9 Hz, 2 H, COCH2),
4.16 (q, J = 7.2 Hz, 2 H, CH2CH3), 4.26 (dt, J = 1.3 Hz and J =
5.7 Hz, 1 H, CH), 6.31 (br s, 1 H, NH), 7.31–7.50 (m, 5 H, Ph)
ppm. 13C NMR (75 MHz, CDCl3): δ = 14.14 (CH3), 26.96 (CH2),
29.53 (CH2), 56.20 (CH), 60.95 (OCH2), 126.21 (CHarom), 128.33
(CHarom), 129.12 (CHarom), 131.38 (Cq. arom), 156.62 (NC=ON),
172.62 (C=O), 172.67 (C=O) ppm. MS (70 eV, ES, Neg): m/z (%)
calcd. C 59.54, H 5.38, N 10.68; found C 59.81, H 5.21, N 10.71.
Ethyl
3-(4-Allyl-2,5-dioxo-1-propylimidazolidin-4-yl)propanoate
1
(13a): Yield: 0.86 g (61%). H NMR (300 MHz, CDCl3): δ = 0.92
(t, J = 7.4 Hz, 3 H, CH2CH2CH3), 1.25 (t, J = 7.2 Hz, 3 H, CH3),
1.63 (sext, J = 7.4 Hz, 2 H, CH2CH2CH3), 2.03–2.29 (m, 4 H,
COCH2CH2), 2.43 (dd, J = 14.0 Hz, J = 7.4 Hz, 1 H, CHAHBCH),
2.50 (dd, J = 14.0 Hz, J = 7.6 Hz, 1 H, CHAHBCH), 3.44 (t, J =
7.4 Hz, 2 H, CH2CH2CH3), 4.13 (q, J = 7.2 Hz, 2 H, CH2CH3),
5.16 (s, 1 H, HC=CHAHB), 5.20 (d, J = 3.3 Hz, 1 H, HC=CHAHB),
5.59–5.73 (m, 1 H, HC=CH2), 5.88 (br s, 1 H, NH) ppm. 13C NMR
= 275.3 (100) [M – H+]. IR (KBr): νmax = 1713 (C=O), 1728 (C=O),
˜
1774 (C=O), 3272 (NH) cm–1. C14H16N2O4 (276.29): calcd. C
60.86, H 5.84, N 10.14; found C 60.84, H 5.76, N 10.05.
Ethyl
3-(1-Benzyl-2,5-dioxo-imidazolidin-4-yl)propanoate
(9e): (75 MHz, CDCl3): δ = 11.23 (CH2CH2CH3), 14.21 (CH3), 21.52
1
Yield: 1.26 g (87%). M.p. 92 °C. H NMR (300 MHz, CDCl3): δ = (CH2CH2CH3), 28.74 (COCH2), 31.05 (COCH2CH2), 40.36
1.24 (t, J = 7.2 Hz, 3 H, CH3), 1.93–2.06 (m, 1 H, CHCHAHB), (CH2CH2CH3), 41.57 (CCH2), 61.04 (CH2CH3), 64.38 (Cq), 121.34
2.15–2.26 (m, 1 H, CHCHAHB), 2.42 (t, J = 7.2 Hz, 2 H, COCH2),
4.07–4.08 (m, 1 H, CH), 4.12 (q, J = 7.2 Hz, 2 H, CH2CH3), 4.64
(HC=CH2), 130.02 (HC=CH2), 156.97 (NC=ON), 172.86 (C=OO),
175.29 (HNC=O) ppm. IR: ν = 1642 (C=C), 1713 (br C=O),
˜
max
Eur. J. Org. Chem. 2006, 2649–2660
© 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
2655

C. V. Stevens et al.
FULL PAPER
1775 (C=O) cm–1. MS: m/z (%)
Chromatography [Hex/EtOAc (1:1)]: Rf
(282.34): calcd. C 59.56, H 7.85, N 9.92; found C 59.16, H 7.75, N
9.89.
=
283.3 (100) [M+H+].
0.42. C14H22N2O4
(d, J = 13.6 Hz, 1 H, CCHAHBCH), 3.43 (dt, J = 2.8 Hz, J = 7.4
Hz, 2 H, CH2CH2CH3), 4.13 (q, J = 7.2 Hz, 2 H, CH2CH3), 4.79
(s, 1 H, C=CHAHB), 4.91 (d, J = 1.1 Hz, 1 H, C=CHAHB), 6.04
(br s, 1 H, NH) ppm. 13C NMR (75 MHz, CDCl3): δ = 11.26
(CH2CH2CH3), 14.19 (CH3), 21.42 (CH2CH2CH3), 24.30 (CH3),
28.76 (COCH2), 31.83 (COCH2CH2), 40.42 (CH2CH2CH3), 44.62
(CCH2), 61.07 (CH2CH3), 64.79 (Cq), 116.98 (C=CH2), 138.75
(C=CH2), 157.39 (NC=ON), 172.87 (C=OO), 175.46 (HNC=O)
=
Ethyl
3-(4-Allyl-2,5-dioxo-1-phenylimidazolidin-4-yl)propanoate
1
(13b): Yield: 1.11 g (70%). H NMR (300 MHz, CDCl3): δ = 1.25
(t, J = 7.1 Hz, 3 H, CH3), 2.12–2.30 (m, 2 H, COCH2CH2), 2.37–
2.41 (m, 2 H, COCH2CH2), 2.51 (dd, J = 13.8 Hz, J = 7.2 Hz, 1
H, CHAHBCH), 2.62 (dd, J = 13.8 Hz, J = 7.7 Hz, 1 H,
CHAHBCH), 4.15 (q, J = 7.1 Hz, 2 H, CH2CH3), 5.23 (s, 1 H,
HC=CHAHB), 5.27 (d, J = 1,9 Hz, 1 H, HC=CHACHB), 5.70–5.84
(m, 1 H, HC=CH2), 6.09 (br s, 1 H, NH), 7.32–7.50 (m, 5 H, Ph)
ppm. IR: ν
= 1646 (C=C), 1713 (br C=O), 1772 (C=O) cm–1.
˜
max
MS: m/z (%) = 297.8 (100) [M+H+]. Chromatography [Hex/EtOAc
(4:6)]: Rf = 0.42. C15H24N2O4 (296.36): calcd. C 60.79, H 8.16, N
9.45; found C 60.54, H 8.00, N 9.36.
ppm. 13C NMR (75 MHz, CDCl3): δ = 14.24 (CH3), 28.90 Typical Experimental Procedure for the Carbamoyllactam Forma-
(COCH2), 31.29 (COCH2CH2), 41.75 (CCH2), 61.17 (CH2CH3), tion from Pyroglutamates: The pyroglutamate ester (1.9 mmol) was
64.49 (Cq), 121.73 (HC=CH2), 126.32 (CHarom.), 128.51 (CHarom.), dissolved in diethyl ether (10 mL, freshly distilled from Na metal)
129.24 (CHarom.), 129.86 (HC=CH2), 131.44 (Cq arom.) ppm. 155.76 and the isocyanate (1.9 mmol) was added followed by NaH
(NC=ON), 172.84 (C=OO), 174.23 (HNC=O). IR: ν
= 1719
(2.09 mmol, washed with hexanes). The mixture was stirred at
˜
max
(C=O), 1781 (C=O) cm–1. MS: m/z (%) = 317.3 (100) [M+H+]. room temperature for 1 h. Then the reaction was quenched by ad-
Chromatography: Hex/EtOAc (1:1) Rf
(316.35): calcd. C 64.54, H 6.37, N 8.86; found C 64.42, H 6.46, N
8.76.
=
0.33. C17H20N2O4
dition of saturated aqueous NH4Cl until the pH was neutral. The
mixture was extracted with diethyl ether, and the organics were
dried (MgSO4) and filtered. The solvent was removed in vacuo.
Ethyl
3-(4-Allyl-1-benzyl-2,5-dioxoimidazolidin-4-yl)propanoate (2S) Ethyl 1-Benzylcarbamoyl-5-oxopyrrolidine-2-carboxylate (10):
1
(13c): Yield: 0.74 g (45%). H NMR (300 MHz, CDCl3): δ = 1.22 Yield: 0.38 g (69%). [α]D = –6.0 (c = 3.0, CH2Cl2). 1H NMR
(t, J = 7.1 Hz, 3 H, CH3), 2.05–2.20 (m, 4 H, COCH2CH2), 2.39 (300 MHz, CDCl3): δ = 1.26 (t, J = 7.2 Hz, 3 H, CH3), 1.96–2.06
(dd, J = 14.0 Hz, J = 7.3 Hz, 1 H, CHAHBCH), 2.47 (dd, J = 14.0 (m, 1 H, CHCHAHB), 2.22–2.36 (m, 1 H, CHCHAHB), 2.51 (ddd,
Hz, J = 7.4 Hz, 1 H, CHAHBCH), 4.09 (q, J = 7.1 Hz, 2 H,
CH2CH3), 4.62 (s, 2 H, CH2Ph), 5.02–5.12 (m, 2 H, HC=CH2),
5.46–5.60 (m, 1 H, HC=CH2), 6.05 (br s, 1 H, NH), 7.23–7.37 (m,
5 H, Ph) ppm. 13C NMR (75 MHz, CDCl3): δ = 14.19 (CH3), 28.67
J = 3.4 Hz, J = 9.4 Hz, J = 18.2 Hz, 1 H, COCHAHB), 2.70 (dt, J
= 8.9, J = 18.2 Hz, 1 H, CHAHB), 4.22 (q, J = 7.2 Hz, 2 H, OCH2),
4.45 (dd, J = 5.9 Hz, J = 15.3 Hz, 1 H, NCHAHB), 4.50 (dd, J =
5.9 Hz, J = 15.3 Hz, 1 H, NCHAHB), 4.77 (dd, J = 2.8 Hz, J =
(COCH2), 31.08 (COCH2CH2), 41.52 (CCH2), 42.35 (CH2Ph), 9.6 Hz, 1 H, CH), 7.20–7.33 (m, 5 H, Ph), 8.70 (br t, J = 5.9 Hz,
61.01 (CH2CH3), 64.55 (Cq), 121.36 (HC=CH2), 127.97 (CHarom.), 1 H, NH) ppm. 13C NMR (75 MHz, CDCl3): δ = 13.92 (CH3),
128.55 (CHarom.), 128.66 (CHarom.), 129.83 (HC=CH2), 136.03 21.07 (CHCH2), 31.58 (COCH2), 43.54 (NCH2), 58.03 (CH), 61.54
(Cq
)
ppm. 156.55 (NC=ON), 172.87 (C=OO), 175.04
(OCH2), 127.19 (CHarom), 127.29 (CHarom), 128.45 (CHarom),
arom.
(HNC=O). IR: νmax = 1713 (C=O), 1774 (C=O) cm–1. MS: m/z (%) 137.97 (Cq,arom), 152.22 (NC=ON), 171.26 (COO), 176.37 (NC=O)
˜
= 331.2 (100) [M+H+]. Chromatography [Hex/EtOAc (55:45)]: Rf
= 0.22. C18H22N2O4 (330.38): calcd. C 65.44, H 6.71, N 8.48; found
C 65.39, H 6.90, N 8.43.
ppm. MS (ES, Pos): m/z (%) = 291.3 (100) [M+H+]. IR: ν
=
˜
max
1694 (C=O), 1723 (C=O), 1746 (C=O), 3314 (br NH) cm–1.
C15H18N2O4 (290.31): calcd. C 62.02, H 6.25, N 9.65; found C
61.69, H 5.93, N 9.68.
Ethyl 3-[4-(2-Chloroprop-2-enyl)-2,5-dioxo-1-propylimidazolidin-4-
yl]propanoate (13d): Yield: 1.05 g (66%). 1H NMR (300 MHz,
(2S) Ethyl 1-Fenylcarbamoyl-5-oxopyrrolidine-2-carboxylate (11):
CDCl3): δ = 0.93 (t, J = 7.4 Hz, 3 H, CH2CH2CH3), 1.24 (t, J = Yield: 0.47 g (89%). [α]D = –19.7 (c = 1.3, CH2Cl2). M.p. 104.2–
1
7.2 Hz, 1.5 H, CH3), 1.25 (t, J = 7.2 Hz, 1.5 H, CH3), 1.64 (sext,
107.6 °C. H NMR (300 MHz, CDCl3): δ = 1.3 (t, J = 7.2 Hz, 3
J = 7.4 Hz, 2 H, CH2CH2CH3), 2.11–2.20 (m, 2 H, COCH2CH2), H, CH3), 2.11 (dddd, J = 2.9 Hz, J = 3.2 Hz, J = 9.6 Hz, J = 13.4
2.23–2.35 (m, 2 H, COCH2CH2), 2.77 (d, J = 14.6 Hz, 1 H, Hz, 1 H, CHCHAHB), 2.39 (dddd, J = 9.7 Hz, J = 9.7 Hz, J = 9.8
CCHAHBC), 2.87 (d, J = 14.6 Hz, 1 H, CCHAHBCH), 3.45 (t, J =
Hz, J = 13.4 Hz, 1 H, CHCHAHB), 2.65 (ddd, J = 3.2 Hz, J = 9.7
7.4 Hz, 2 H, CH2CH2CH3), 4.12 (q, J = 7.2 Hz, 1 H, CHAHBCH3), Hz, J = 17.7 Hz, 1 H, COCHAHB), 2.84 (ddd, J = 9.6 Hz, J = 9.8
4.13 (q, J = 7.2 Hz, 2 H, CHAHBCH3), 5.28 (s, 1 H, HC=CHAHB),
5.34 (d, J = 3.3 Hz, 1 H, HC=CHAHB), 6.48 (br s, 1 H, NH)
ppm. 13C NMR (75 MHz, CDCl3): δ = 11.28 (CH2CH2CH3), 14.18
Hz, J = 17.7 Hz, 1 H, COCHAHB), 4.26 (q, J = 7.2 Hz, 2 H,
OCH2), 4.87 (dd, J = 2.9 Hz, J = 9.7 Hz, 1 H, CH), 7.10–7.53 (m,
5 H, Ph), 10.42 (br s, NH) ppm. 13C NMR (75 MHz, CDCl3): δ =
(CH3), 21.35 (CH2CH2CH3), 28.54 (COCH2), 31.34 (COCH2CH2), 14.11 (CH3), 21.13 (CHCH2), 31.96 (COCH2), 58.20 (CH), 61.88
40.53 (CH2CH2CH3), 45.97 (CCH2), 61.05 (CH2CH3), 63.80 (Cq), (OCH2), 120.16 (CHarom), 124.27 (CHarom), 129.00 (CHarom),
118.37 (HC=CH2), 135.25 (HC=CH2), 156.90 (NC=ON), 172.55
137.17 (Cq,arom), 149.57 (NC=ON), 171.19 (COO), 176.71 (NCO)
(C=OO), 174.75 (HNC=O) ppm. IR: νmax = 1633 (C=C), 1717 (br ppm. MS (ES, Pos): m/z (%) = 277.2 (100) [M+H+]. IR: ν
=
˜
˜
max
C=O), 1777 (C=O) cm–1. MS: m/z (%) = 317.7/319.8 (100)
1702 (C=O), 1717 (C=O), 1739 (C=O), 3300 (br NH) cm–1.
C14H16N2O4 (276.11): calcd. C 60.86, H 5.84, N 10.14; found C
[M+H+]. Chromatography [Hex/EtOAc (6:4)]: Rf
= 0.26.
C14H21ClN2O4 (316.78): calcd. C 59.08, H 6.68, N 8.84; found C 61.48, H 5.69, N 10.21.
58.97, H 6.78, N 8.74.
Typical Experimental Procedure for the N-Alkylation of Ethyl 3-
Ethyl 3-[4-(2-Methylprop-2-enyl)-2,5-dioxo-1-propylimidazolidin-4- [1,4-Dialkyl-2,5-dioxo-1-imidazolidin-4-yl]propanoates (13): The hy-
yl]propanoate (13e): Yield: 0.93 g (63%). 1H NMR (300 MHz,
dantoin (13) (3 mmol) was dissolved in acetone (10 mL) and the
CDCl3): δ = 0.92 (t, J = 7.4 Hz, 3 H, CH2CH2CH3), 1.25 (t, J = alkyl halide (9 mmol) was added followed by K2CO3 (15 mmol,
7.2 Hz, 1.5 H, CH3), 1.26 (t, J = 7.2 Hz, 1.5 H, CH3), 1.62 (sext, finely ground). The mixture was refluxed until TLC analysis
J = 7.4 Hz, 2 H, CH2CH2CH3), 1.73 (s, 3 H, CCH3), 2.08–2.28 (m, showed that all starting material was consumed. The mixture was
4 H, COCH2CH2), 2.38 (d, J = 13.6 Hz, 1 H, CCHAHBC), 2.55 filtered and the solvent was removed in vacuo. If necessary the
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© 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2006, 2649–2660

The Pyroglutamate Hydantoin Rearrangement
FULL PAPER
residue was purified by flash chromatography (silica gel; hexane/
EtOAc).
(300 MHz, CDCl3): δ = 1.24 (t, J = 7.2 Hz, 3 H, CH3), 1.86 (s, 3
H, CCH3), 2.18–2.38 (m, 4 H, COCH2CH2), 2.63–2.67 (m, 2 H,
CH2CH), 3.86 (d, J = 15.3 Hz, 1 H, NCHAHBC), 4.03 (d, J = 15.3
Hz, 1 H, NCHAHBC), 4.12 (q, J = 7.2 Hz, 2 H, CH2CH3), 4.96 (s,
1 H, C=CHAHB), 5.02 (s, 1 H, C=CHAHB), 5.19 (d, J = 3.9 Hz, 1
H, HC=CHAHB), 5.24 (d, J = 10.7 Hz, 1 H, HC=CHAHB), 5.55–
5.69 (m, 1 H, HC=CH2), 7.31–7.48 (m, 5 H, Ph) ppm. 13C NMR
(75 MHz, CDCl3): δ = 14.23 (CH3), 20.89 (CCH3), 28.53 (COCH2),
29.95 (COCH2CH2), 39.72 (CCH2CH), 46.41 (NCH2C), 60.97
(CH2CH3), 68.44 (Cq), 114.96 (C=CH2), 121.42 (HC=CH2), 126.17
(CHarom.), 128.32 (CHarom.), 129.12 (CHarom.), 129.83 (HC=CH2),
131.65 (Cq arom.) ppm. 141.50 (C=CH2), 155.80 (NC=ON), 172.00
Ethyl 3-(3,4-Diallyl-2,5-dioxo-1-propylimidazolidin-4-yl)propanoate
(14a): Yield: 0.97 g (100%).1H NMR (300 MHz, CDCl3): δ = 0.91
(t, J = 7.4 Hz, 3 H, CH2CH2CH3), 1.24 (t, J = 7.2 Hz, 3 H, CH3),
1.61 (sext, J = 7.3 Hz, 2 H, CH2CH2CH3), 2.05–2.20 (m, 4 H,
COCH2CH2), 2.46–2.60 (m, 2 H, CCH2), 3.44 (dt, J = 7.4 Hz, J =
1.7 Hz, 2 H, NCH2CH2), 3.82 (dd, J = 15.6 Hz, J = 6.9 Hz, 1 H,
NCHAHBCH), 4.01 (dd, J = 15.6 Hz, J = 6.5 Hz, 1 H,
NCHAHBCH), 4.11 (q, J = 7.2 Hz, 2 H, CH2CH3), 5.10–5.35 (m,
4 H, 2×HC=CH2), 5.42–5.56 (m, 1 H, HC=CH2), 5.85–5.99 (m, 1
H, HC=CH2) ppm. 13C NMR (75 MHz, CDCl3): δ = 11.35
(CH2CH2CH3), 14.22 (CH3), 21.57 (CH2CH2CH3), 28.33
(COCH2), 29.77 (COCH2CH2), 39.54 (CCH2CH), 40.58
(CH2CH2CH3), 42.87 (NCH2CH), 60.90 (CH2CH3), 68.09 (Cq),
118.93 (HC=CH2), 121.01 (HC=CH2), 129.88 (HC=CH2), 133.32
(HC=CH2), 156.39 (NC=ON), 172.05 (C=OO), 174.19 (NC=O)
(C=OO), 173.33 (NC=O). IR: ν
= 1717 (br C=O), 1773 (C=O)
˜
max
cm–1. MS: m/z (%) = 371.2 (100) [M+H+]. C21H26N2O4 (370.44):
calcd. C 68.09, H 7.07, N 7.56; found C 67.93, H 6.97, N 7.55.
Ethyl 3-{4-Allyl-1-benzyl-3-[2-(chloromethyl)prop-2-enyl]-2,5-dioxo-
imidazolidin-4-yl}propanoate (14e): Yield: 0.90 g (72%). 1H NMR
(300 MHz, CDCl3): δ = 1.22 (t, J = 7.1 Hz, 3 H, CH3), 2.01–2.20
(m, 4 H, COCH2CH2), 2.48 (dd, J = 14.5 Hz, J = 7.4 Hz, 1 H,
CHAHBCH), 2.56 (dd, J = 14.5 Hz, J = 6.9 Hz, 1 H, CHAHBCH),
3.89–4.12 (m, 4 H, NCH2CCH2Cl), 4.09 (q, J = 7.1 Hz, 2 H,
CH2CH3), 4.64 (s, 2 H, NCH2Ph), 4.79–5.08 (m, 2 H, HC=CH2),
5.23 (s, 1 H, C=CHAHB), 5.23–5.37 (m, 1 H, HC=CH2), 5.37 (s, 1
H, C=CHAHB), 7.25–7.40 (m, 5 H, Ph) ppm. 13C NMR (75 MHz,
CDCl3): δ = 14.22 (CH3), 28.32 (COCH2), 29.71 (COCH2CH2),
39.52 (CCH2CH), 42.21 (NCH2CH), 42.73 (NCH2Ph), 45.98
(CH2Cl), 60.89 (CH2CH3), 68.55 (Cq), 118.50 (C=CH2), 121.27
(HC=CH2), 128.06 (CHarom.), 128.69 (CHarom.), 128.78 (CHarom.),
129.51 (HC=CH2), 135.94 (Cq arom.) ppm. 140.87 (C=CH2), 156.81
ppm. IR: ν
= 1643 (C=C), 1709 (C=O), 1735 (C=O), 1768
˜
max
(C=O) cm–1. MS: m/z (%) = 323.3 (100) [M+H+]. Chromatography
[Hex/EtOAc (6:4)]: Rf = 0.52. C17H26N2O4 (322.40): calcd. C 63.33,
H 8.13, N 8.69; found C 62.98, H 8.01, N 8.66.
Ethyl 3-(3,4-Diallyl-2,5-dioxo-1-phenylimidazolidin-4-yl)propanoate
(14b): Yield: 1.07 g (100%). 1H NMR (300 MHz, CDCl3): δ = 1.24
(t, J = 7.1 Hz, 3 H, CH3), 2.14–2.38 (m, 4 H, COCH2CH2), 2.60
(dd, J = 14.2 Hz, J = 6.5 Hz, 1 H, CCHAHB), 2.67 (dd, J = 14.2
Hz, J = 8.0 Hz, 1 H, CCHAHB), 3.91 (dd, J = 15.4 Hz, J = 6.9
Hz, 1 H, NCHAHBCH), 4.09 (dd, J = 15.4 Hz, J = 6.6 Hz, 1 H,
NCHAHBCH), 4.13 (q, J = 7.1 Hz, 2 H, CH2CH3), 5.19–5.40 (m,
4 H, 2×HC=CH2), 5.57–5.71 (m, 1 H, HC=CH2), 5.92–6.06 (m, 1
H, HC=CH2), 7.32–7.48 (m, 5 H, Ph) ppm. 13C NMR (75 MHz,
CDCl3): δ = 14.24 (CH3), 28.48 (COCH2), 29.97 (COCH2CH2),
39.78 (CCH2CH), 43.16 (NCH2CH), 61.00 (CH2CH3), 68.18 (Cq),
119.28 (HC=CH2), 121.42 (HC=CH2), 126.22 (CHarom.), 128.35
(NC=ON), 171.87 (C=OO), 173.94 (NC=O). IR: ν
= 1710 (br
˜
max
C=O), 1769 (C=O) cm–1. MS: m/z (%) = 419.2/421.3 (100)
[M+H+]. Chromatography [Hex/EtOAc (6:4)]: Rf
=
0.63.
C22H27N2O4 (418.91): calcd. C 63.08, H 6.50, N 6.69; found C
62.94, H 6.55, N 6.72.
(CHarom.), 129.13 (CHarom.), 129.77 (HC=CH2), 131.52 (Cq arom.
)
ppm. 133.04 (HC=CH2), 155.22 (NC=ON), 171.99 (C=OO),
Ethyl 2-{[5-Allyl-3-benzyl-5-(3-ethoxy-3-oxopropyl)-2,4-dioxoimid-
azolidin-1-yl]methyl}acrylate (14f): Yield: 0.60 g (45%). 1H NMR
(300 MHz, CDCl3): δ = 1.16–1.32 (m, 6 H, 2×CH2CH3), 1.94–2.15
(m, 4 H, COCH2CH2), 2.60 (dd, J = 14.2 Hz, J = 6.5 Hz, 1 H,
CCHAHB), 2.52 (d, J = 7.2 Hz, 2 H, CCH2), 4.02–4.16 (m, 3 H,
NCHAHB + CH2CH3), 4.19–4.26 (m, 3 H, NCHAHB + CH2CH3),
4.64 (s, 2 H, CH2Ph), 4.91–5.07 (m, 2 H, HC=CH2), 5.22–5.36 (m,
1 H, HC=CH2), 5.99 (d, J = 0.8 Hz, 1 H, C=CHAHB), 6.42 (s, 1
H, C=CHAHB), 7.24–7.39 (m, 5 H, Ph) ppm. 13C NMR (75 MHz,
CDCl3): δ = 14.21 (2×CH3), 28.36 (COCH2), 29.75 (COCH2CH2),
39.40 (CCH2CH), 39.75 (NCH2CH), 42.67 (CH2Ph), 60.79
(CH2CH3), 61.36 (CH2CH3), 68.43 (Cq), 121.09 (HC=CH2), 128.00
(CHarom.), 128.64 (CHarom.), 128.73 (CHarom.), 129.60 (C=CH2),
129.67 (HC=CH2), 136.02 (Cq arom.) ppm. 156.64 (NC=ON),
173.23 (NC=O). IR: ν
= 1642 (C=C), 1717 (br C=O), 1772
˜
max
(C=O) cm–1. MS: m/z (%) = 357.2 (100) [M+H+]. C20H24N2O4
(356.42): calcd. C 67.40, H 6.79, N 7.86; found C 67.08, H 6.74, N
7.84.
Ethyl 3-[4-Allyl-1-benzyl-3-(2-chloroprop-2-enyl)-2,5-dioxo-1-phen-
1
ylimidazolidin-4-yl]propanoate (14c): Yield: 0.85 g (70%). H NMR
(300 MHz, CDCl3): δ = 1.22 (t, J = 7.0 Hz, 3 H, CH3), 2.00–2.28
(m, 4 H, COCH2CH2), 2.50 (dd, J = 14.5 Hz, J = 7.2 Hz, 1 H,
CCHAHB), 2.58 (dd, J = 14.5 Hz, J = 7.3 Hz, 1 H, CCHAHB),
3.90 (d, J = 15.8 Hz, 1 H, NCHAHBC), 4.09 (q, J = 7.0 Hz, 2 H,
CH2CH3), 4.27 (d, J = 15.8 Hz, 1 H, NCHAHBC), 4.62 (d, J =
14.4 Hz, 1 H, NCHAHBPh), 4.68 (d, J = 14.4 Hz, 1 H,
NCHAHBPh), 4.93–5.10 (m, 2 H, HC=CH2), 5.28–5.39 (m, 1 H,
HC=CH2), 5.42 (d, J = 1.8 Hz, 1 H, C=CHAHB), 5.50 (d, J = 1.8
Hz, 1 H, C=CHAHB), 7.25–7.39 (m, 5 H, Ph) ppm. 13C NMR
(75 MHz, CDCl3): δ = 14.22 (CH3), 28.33 (COCH2), 29.95
(COCH2CH2), 39.54 (CCH2CH), 42.79 (NCH2Ph), 46.50
(NCH2C), 60.84 (CH2CH3), 68.38 (Cq), 116.72 (C=CH2), 121.28
(HC=CH2), 128.06 (CHarom.), 128.67 (CHarom.), 128.75 (CHarom.),
129.44 (HC=CH2), 135.88 (Cq arom.) ppm. 137.45 (CCl), 156.52
165.99 (CC=O), 171.85 (C=OO), 174.00 (NC=O). IR: νmax = 1662
˜
(C=C), 1711 (br C=O), 1770 (C=O) cm–1. MS: m/z (%) = 443.2
(100) [M+H+]. Chromatography [Hex/EtOAc/ether (9:1:2)]: Rf =
0.07. C24H30N2O4 (442.50): calcd. C 65.14, H 6.83, N 6.33; found
C 65.09, H 6.85, N 6.23.
Ethyl
3-[3-Allyl-4-(2-chloroprop-2-enyl)-2,5-dioxo-1-propylimid-
azolidin-4-yl]propanoate (14g): Yield: 0.89 g (83%). 1H NMR
(300 MHz, CDCl3): δ = 0.92 (t, J = 7.4 Hz, 3 H, CH2CH2CH3),
1.24 (t, J = 7.1 Hz, 1.5 H, CH3), 1.25 (t, J = 7.1 Hz, 1.5 H, CH3),
1.63 (sext, J = 7.4 Hz, 2 H, CH2CH2CH3), 2.01–2.25 (m, 4 H,
COCH2CH2), 2.80 (d, J = 14.9 Hz, 1 H, CCHAHB), 2.95 (d, J =
14.9 Hz, 1 H, CCHAHB), 3.42 (dt, J = 7.4 Hz, J = 11.8 Hz, 1 H,
NCHAHBCH2), 3.48 (dt, J = 7.4 Hz, J = 11.8 Hz, 1 H,
NCHAHBCH2), 3.65 (dd, J = 15.6 Hz, J = 7.8 Hz, 1 H,
(NC=ON), 172.03 (C=OO), 173.73 (NC=O). IR: ν
= 1635
˜
max
(C=C), 1713 (br C=O), 1772 (C=O) cm–1. MS: m/z (%) = 405.2
(100) [M+H+], 407.2 (29) [M+H+]. Chromatography [Hex/EtOAc
(7:3)]: Rf = 0.35. C21H25ClN2O4 (404.89): calcd. C 62.30, H 6.22,
N 6.92; found C 62.55, H 6.14, N 6.86.
Ethyl
3-[4-Allyl-3-(2-methylprop-2-enyl)-2,5-dioxo-1-phenylimid-
azolidin-4-yl]propanoate (14d): Yield: 1.11 g (100%). 1H NMR
Eur. J. Org. Chem. 2006, 2649–2660
© 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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2657

C. V. Stevens et al.
NCHAHBCH), 4.11 (q, J = 7.1 Hz, 2 H, CH2CH3), 4.28 (dd, J = 113 °C. 1H NMR (300 MHz, CDCl3): δ = 1.23 (t, J = 7.2 Hz, 3 H,
FULL PAPER
15.6 Hz, J = 5.5 Hz, 1 H, NCHAHBCH), 5.19–5.35 (m, 4 H,
CH2CH3), 2.19–2.56 (m, 6 H, COCH2CH2 and CCH2), 3.65 (d, J
C=CH2 + HC=CH2), 5.89–6.02 (m, 1 H, HC=CH2) ppm. 13C = 19.9 Hz + small splitting, 1 H, NCHAHB), 4.12 (q, J = 7.2 Hz,
NMR (75 MHz, CDCl3): δ = 11.32 (CH2CH2CH3), 14.19 (CH3), 2 H, CH2CH3), 4.48 (d, J = 19.9 Hz, 1 H, NCHAHB), 5.78 (m, 1
21.32 (CH2CH2CH3), 27.92 (COCH2), 30.32 (COCH2CH2), 40.70
(CH2CH2CH3), 43.54 (CCH2C + NCH2CH), 60.84 (CH2CH3), δ = 14.22 (CH2CH3), 28.94 (COCH2), 28.99 (COCH2CH2), 31.83
67.49 (Cq), 118.14 (C=CH2), 119.02 (HC=CH2), 133.13 (CCH2CH), 38.04 (NCH2), 60.39 (Cq), 61.08 (CH2CH3), 121.71
(HC=CH2), 135.09 (C=CH2), 156.14 (NC=ON), 171.73 (C=OO), (CH), 123.25 (CH), 126.25 (CHarom.), 128.32 (CHarom.), 129.16
H, CH), 7.35–7.50 (m, 5 H, Ph) ppm. 13C NMR (75 MHz, CDCl3):
173.45 (NC=O) ppm. IR: ν
= 1632 (C=C), 1709 (C=O), 1735
(CHarom.), 131.65 (Cq arom.), 153.99 (NC=ON), 172.42 (C=OO),
˜
max
(C=O), 1770 (C=O) cm–1. MS: m/z (%) = 357.7/359.7 (100)
174.62 (NC=O) ppm. IR: νmax = 1721 (br C=O), 1775 (C=O) cm–1.
˜
[M+H+]. Chromatography [Hex/EtOAc (2:1)]: Rf
=
0.43.
MS: m/z (%) = 329.2 (100) [M+H+]. Chromatography [Hex/EtOAc
C17H25ClN2O4 (356.84): calcd. C 57.22, H 7.06, N 7.85; found C (7:3)]: Rf = 0.21. C18H20N2O4 (328.36): calcd. C 65.84, H 6.14, N
56.89, H 6.90, N 7.83.
8.53; found C 65.70, H 6.34, N 8.45.
Ethyl
3-[3-Allyl-4-(2-methylprop-2-enyl)-2,5-dioxo-1-propylimid-
Ethyl 3-[2-Benzyl-6-chloro-1,3-dioxo-2,3,5,8-tetrahydroimidazo[1,5-
a]pyridin-8a(1H)-yl]propanoate (15c): Instead of refluxing in
CH2Cl2, the reaction is refluxed in dry benzene for 16 hours. Yield:
0.17 g (75%). 1H NMR (300 MHz, CDCl3): δ = 1.20 (t, J = 7.1
Hz, 3 H, CH3), 2.00–2.33 (m, 4 H, COCH2CH2), 2.39–2.41 (m, 2
azolidin-4-yl]propanoate (14h): Yield: 1.01 g (100%). 1H NMR
(300 MHz, CDCl3): δ = 0.91 (t, J = 7.4 Hz, 3 H, CH2CH2CH3),
1.24 (t, J = 7.2 Hz, 3 H, CH3), 1.61 (sext, J = 7.4 Hz, 2 H,
CH2CH2CH3), 1.63 (s,
3 H, CCH3), 1.96–2.22 (m, 4 H,
COCH2CH2), 2.49 (d, J = 14.4 Hz, 1 H, CCHAHB), 2.57 (d, J =
14.4 Hz, 1 H, CCHAHB), 3.41 (dt, J = 7.4 Hz, J = 13.5 Hz, 1 H,
NCHAHBCH2), 3.45 (dt, J = 7.4 Hz, J = 13.5 Hz, 1 H,
NCHAHBCH2), 3.61 (dd, J = 15.4 Hz, J = 7.7 Hz, 1 H,
NCHAHBCH), 4.11 (q, J = 7.2 Hz, 2 H, CH2CH3), 4.21 (ddt, J =
15.4 Hz, J = 5.5 Hz, J = 1.4 Hz, 1 H, NCHAHBCH), 4.72 (d, J =
0.8 Hz, 1 H, C=CHAHB), 4.86 (t, J = 1.5 Hz, 1 H, C=CHAHB),
5.20 (dd, J = 9.9 Hz, J = 0.8 Hz, 1 H, HC=CHAHB), 5.31 (dq, J
= 17.0 Hz, J = 1.4 Hz, 1 H, HC=CHAHB), 5.87–6.00 (m, 1 H,
H, CH2CH), 3.63 (dq,
J = 17.9 Hz, J = 2.6 Hz, 1 H,
NCHAHBCCl), 4.07 (q, J = 7.1 Hz, 2 H, CH2CH3), 4.49 (dq, J =
17.9 Hz, J = 2.2 Hz, 1 H, NCHAHBCCl), 4.67 (s, 2 H, NCH2Ph),
5.86 (dq, J = 1.6 Hz, J = 3.5 Hz, 1 H, CH), 7.27–7.39 (m, 5 H,
Ph) ppm. 13C NMR (75 MHz, CDCl3): δ = 14.19 (CH3), 28.48
(COCH2), 28.71 (COCH2CH2), 32.61 (CCH2CH), 41.87 (NCH2C),
42.64 (NCH2Ph), 60.07 (Cq), 61.02 (CH2CH3), 119.28 (CH), 127.31
(CCl), 128.14 (CHarom.), 128.52 (CHarom.), 128.83 (CHarom.), 135.91
(Cq arom.), 154.51 (NC=ON), 172.20 (C=OO), 174.49 (NC=O)
HC=CH2) ppm. 13C NMR (75 MHz, CDCl3):
δ = 11.34
ppm. IR: ν
= 1660 (C=C), 1714 (br C=O), 1775 (C=O) cm–1.
˜
max
(CH2CH2CH3), 14.24 (CH3), 21.45 (CH2CH2CH3), 23.67 (CCH3),
28.13 (COCH2), 30.88 (COCH2CH2), 40.58 (CH2CH2CH3), 42.45
(CCH2C), 43.23 (NCH2CH), 60.82 (CH2CH3), 67.97 (Cq), 116.58
(C=CH2), 118.96 (HC=CH2), 133.19 (HC=CH2), 138.77 (C=CH2),
MS: m/z (%) = 377.2/379.2 (100) [M+H+]. Chromatography [Hex/
EtOAc (7:3)]: Rf = 0.29. C19H21ClN2O4 (376.83): calcd. C 60.56, H
5.62, N 7.43; found C 60.44, H 5.74, N 7.37.
156.32 (NC=ON), 172.00 (C=OO), 174.39 (NC=O) ppm. IR: ν
Ethyl 3-[6-Methyl-1,3-dioxo-2-phenyl-2,3,5,8-tetrahydroimidazo[1,5-
˜
max
= 1645 (C=C), 1708 (C=O), 1735 (C=O), 1767 (C=O) cm–1. MS: a]pyridin-8a(1H)-yl]propanoate (15d): Yield: 0.16 g (79%). 1H
m/z (%) = 337.8 (100) [M+H+]. C18 H28N2O4 (336.43): calcd. C
64.26, H 8.39, N 8.33; found C 64.22, H 8.55, N 8.28.
NMR (300 MHz, CDCl3): δ = 1.23 (t, J = 7.2 Hz, 3 H, CH2CH3),
1.76 (s, 3 H, CCH3), 2.19–2.52 (m, 6 H, COCH2CH2 and CCH2),
3.50 (d, J = 18.0 Hz, 1 H, NCHAHB), 4.12 (q, J = 7.2 Hz, 2 H,
CH2CH3), 4.34 (d, J = 18.0 Hz, 1 H, NCHAHB), 5.51 (t, J = 1.9
Hz, 1 H, CH), 7.35–7.49 (m, 5 H, Ph) ppm. 13C NMR (75 MHz,
CDCl3): δ = 14.22 (CH2CH3), 20.21 (CCH3), 28.79 (COCH2), 29.05
(COCH2CH2), 31.89 (CCH2CH), 41.39 (NCH2), 60.29 (Cq), 61.07
(CH2CH3), 116.05 (CH), 126.26 (CHarom.), 128.31 (CHarom.),
129.16 (CHarom.), 130.57 (CCH3), 131.68 (Cq arom.), 153.96
Typical Experimental Procedure for the Synthesis of Ethyl 3-(2,6-
Dialkyl-1,3-dioxo-2,3,5,8-tetrahydroimidazo[1,5-a]pyridin-8a(1H)-
yl)propanoates (15): The hydantoin 14 (0.6 mmol) was dissolved in
CH2Cl2 (10 mL, freshly distilled from CaH2) and the second gener-
ation Grubbs’ catalyst (0.03 mmol) was added. The mixture was
refluxed under N2 for 4 h. The residue was adsorbed onto silica gel
by removal of the solvent in vacuo and purified by flash
chromatography (silica gel; hexane/EtOAc).
(NC=ON), 172.51 (C=OO), 174.74 (NC=O) ppm. IR: νmax = 1721
˜
(br C=O), 1775 (C=O) cm–1. MS: m/z (%) = 343.2 (100) [M+H+].
Ethyl
3-[1,3-Dioxo-2-propyl-2,3,5,8-tetrahydroimidazo[1,5-a]pyri-
Chromatography [Hex/EtOAc (7:3)]: Rf
= 0.29. C19H22N2O4
din-8a(1H)-yl]propanoate (15a): Yield: 0.16 g (93%). 1H NMR
(300 MHz, CDCl3): δ = 0.93 (t, J = 7.4 Hz, 3 H, CH3 pr), 1.24 (t,
J = 7.1 Hz, 3 H, CH2CH3), 1.66 (sext, J = 7.4 Hz, 2 H, NCH2CH2),
2.05–2.33 (m, 6 H, COCH2CH2 and CCH2), 3.49 (dt, J = 7.4 Hz,
J = 1.6 Hz, 2 H, NCH2CH2), 3.56 (d, J = 18.2 Hz + small splitting,
1 H, NCHAHB), 4.10 (q, J = 7.1 Hz, 2 H, CH2CH3), 4.41 (d, J =
18.2 Hz + small splitting, 1 H, NCHAHB), 5.78 (t, J = 1.9 Hz +
small splitting, 2 H, HC=CH) ppm. 13C NMR (75 MHz, CDCl3):
δ = 11.22 (CH3 pr), 14.15 (CH2CH3), 21.53 (CH2 pr), 28.43
(COCH2), 28.80 (COCH2CH2), 31.65 (CCH2CH), 37.71 (NCH2),
40.37 (NCH2 pr), 60.28 (Cq), 60.87 (CH2CH3), 121.59 (CH), 123.27
(CH), 155.15 (NC=ON), 172.39 (C=OO), 175.74 (NC=O) ppm.
(342.39): calcd. C 66.65, H 6.48, N 8.18; found C 66.25, H 6.39, N
8.17.
Ethyl
3-[2-Benzyl-6-(chloromethyl)-1,3-dioxo-2,3,5,8-tetrahydro-
imidazo[1,5-a]pyridin-8a(1H)-yl]propanoate (15e): Yield: 0.20 g
1
(85%). H NMR (300 MHz, CDCl3): δ = 1.20 (t, J = 7.1 Hz, 3 H,
CH2CH3), 2.05–2.21 (m, 4 H, COCH2CH2), 2.23–2.43 (m, 2 H,
CCH2), 3.59 (dq, J = 18.0 Hz, J = 2.4 Hz, 1 H, NCHAHB), 4.05
(s, 2 H, CH2Cl), 4.07 (q, J = 7.1 Hz, 2 H, CH2CH3), 4.54 (d, J =
18.0 Hz, 1 H, NCHAHB), 4.67 (d, J = 15.0 Hz, 1 H, NCHAHBPh),
4.68 (d, J = 15.0 Hz, 1 H, NCHAHBPh), 5.88 (q-like, J = 2.4 Hz,
1 H, CH), 7.28–7.41 (m, 5 H, Ph) ppm. 13C NMR (75 MHz,
IR: ν
= 1656 (C=C), 1709 (br C=O), 1771 (C=O) cm–1. MS:
˜
max
CDCl3):
δ
=
14.21 (CH2CH3), 28.62 (COCH2), 28.73
m/z (%) = 295.2 (100) [M+H+]. Chromatography [Hex/EtOAc
(6:4)]: Rf = 0.25. C15H22N2O4 (294.35): calcd. C 61.21, H 7.53, N
9.52; found C 60.92, H 7.62, N 9.48.
(COCH2CH2), 31.58 (CCH2CH), 38.38 (NCH2), 42.56 (NCH2Ph),
45.83 (CH2Cl), 60.30 (Cq), 60.97 (CH2CH3), 121.85 (CH), 128.06
(CHarom.), 128.55 (CHarom.), 128.80 (CHarom.), 131.45 (CCH2Cl),
136.08 (Cq arom.), 154.77 (NC=ON), 172.33 (C=OO), 175.00
Ethyl
3-[1,3-Dioxo-2-phenyl-2,3,5,8-tetrahydroimidazo[1,5-a]pyri-
din-8a(1H)-yl]propanoate (15b): Yield: 0.17 g (88%). M.p. 110–
(NC=O) ppm. IR: ν
= 1713 (br C=O), 1771 (C=O) cm–1. MS:
˜
max
2658
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© 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2006, 2649–2660

The Pyroglutamate Hydantoin Rearrangement
m/z (%) = 391.2/393.2 (100) [M+H+]. Chromatography [Hex/ (CCH3), 28.73 (COCH2), 28.85 (COCH2CH2), 35.95 (CCH2C),
FULL PAPER
EtOAc (7:3)]: Rf = 0.18. C20H23ClN2O4 (390.86): calcd. C 61.46, H
37.43 (NCH2), 40.12 (NCH2 pr), 60.41 (CH2CH3), 60.64 (Cq),
5.93, N 7.17; found C 61.19, H 5.85, N 7.13.
116.83 (CH), 128.83 (C), 154.98 (NC=ON), 171.90 (C=OO), 175.26
(NC=O) ppm. IR: ν
= 1712 (br C=O), 1770 (C=O) cm–1. MS:
˜
max
Ethyl
2-Benzyl-8a-(3-ethoxy-3-oxopropyl)1,3-dioxo-1,2,3,5,8,8a-
m/z (%) = 309.8 (100) [M+H+]. Chromatography [Hex/EtOAc
(7:3)]: Rf = 0.27. C16H24N2O4 (308.37): calcd. C 62.32, H 7.84, N
9.08; found C 62.38, H 8.00, N 9.10.
hexahydroimidazo[1,5-a]pyridine-6-carboxylate (15f): Instead of the
second generation Grubbs’ catalyst, the second generation Hov-
eyda-Grubbs’ catalyst is used for this reaction. Yield: 0.14 g (55%).
1H NMR (300 MHz, CDCl3): δ = 1.20 (t, J = 7.2 Hz, 3 H,
CH2CH3), 1.30 (t, J = 7.0 Hz, 3 H, CH2CH3), 2.04–2.17 (m, 4 H,
COCH2CH2), 2.41 (dq, J = 18.4 Hz, J = 2.8 Hz, 1 H, CCHAHB),
2.54 (dd, J = 18.4 Hz, J = 5.5 Hz, 1 H, CCHAHB), 3.73 (ddt, J =
18.7 Hz, J = 3.7 Hz, J = 4.1 Hz, 1 H, NCHAHB), 4.07 (q, J = 7.2
Hz, 2 H, CH2CH3), 4.21 (dq, J = 10.6 Hz, J = 7.0 Hz, 1 H,
CHAHBCH3), 4.25 (dq, J = 10.6 Hz, J = 7.1 Hz, 1 H, CHAHBCH3),
4.68 (s, 2 H, NCH2Ph), 4.70 (dt, J = 18.7 Hz, J = 1.9 Hz, 1 H,
NCHAHB), 6.98 (dd, J = 5.8 Hz, J = 2.2 Hz, 1 H, CH), 7.29–7.59
(m, 5 H, Ph) ppm. 13C NMR (75 MHz, CDCl3): δ = 14.19
(CH2CH3), 14.27 (CH2CH3), 28.61 (COCH2), 28.76 (COCH2CH2),
32.09 (CCH2CH), 36.91 (NCH2), 42.58 (NCH2Ph), 59.92 (Cq),
Acknowledgments
The authors thank the BOF (Bijzonder Onderzoeksfonds Uni-
versiteit Gent, Research Fund Ghent University) and the FWO
(Fonds voor Wetenschappelijk Onderzoek - Vlaanderen, Fund for
Scientific Research – Flanders) for financial support of this re-
search.
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128.80 (CH), 133.42 (HC=C), 136.03 (HC=C), 137.67 (Cq,ar),
154.61 (NC=ON), 164.28 (CCOOEt), 172.13 (C=OO), 174.68
(NC=O) ppm. IR: νmax = 1659 (C=C), 1716 (br C=O), 1774 (C=O)
˜
cm–1. MS: m/z (%) = 415.3 (100) [M+H+]. Chromatography: first
Hex/EtOAc (3:1) until Rf = 0.26, then strip with EtOAc + 5%
CH2Cl2. C22H26N2O4 (414.45): calcd. C 63.76, H 6.32, N 6.76;
found C 63.54, H 6.51, N 6.72.
Ethyl 3-[7-Chloro-1,3-dioxo-2-propyl-2,3,5,8-tetrahydroimidazo[1,5-
a]pyridin-8a(1H)-yl]propanoate (15g): Instead of refluxing in
CH2Cl2, the reaction is refluxed in dry benzene for 16 hours. Yield:
0.15 g (77%). 1H NMR (300 MHz, CDCl3): δ = 0.93 (t, J = 7.4
Hz, 3 H, CH2CH2CH3), 1.24 (t, J = 7.2 Hz, 3 H, CH2CH3), 1.66
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(sext,
J = 7.4 Hz, 2 H, NCH2CH2), 2.07–2.36 (m, 4 H,
COCH2CH2), 2.51 (d, J = 17.4 Hz, 1 H, CCHAHBC), 2.64 (dq, J
= 17.4 Hz, J = 3.1 Hz, 1 H, CCHAHBC), 3.49 (dt, J = 7.4 Hz, J
= 2.2 Hz, 2 H, NCH2CH2), 3.61 (dq, J = 18.4 Hz, J = 3.2 Hz, 1
H, NCHAHB), 4.11 (q, J = 7.2 Hz, 2 H, CH2CH3), 4.49 (dt, J =
18.4 Hz, J = 3.2 Hz, 1 H, NCHAHB), 5.90 (q, J = 3.2 Hz, 1 H,
CH) ppm. 13C NMR (75 MHz, CDCl3): δ = 11.26 (CH3 pr), 14.21
(CH2CH3), 21.52 (CH2 pr), 28.70 (COCH2CH2), 38.16 (NCH2),
38.77 (CCH2C), 40.64 (NCH2 pr), 61.08 (CH2CH3), 61.55 (Cq),
120.17 (CH), 126.86 (CCl), 154.97 (NC=ON), 172.20 (C=OO),
174.29 (NC=O) ppm. IR: νmax = 1663 (C=C), 1713 (br C=O), 1774
˜
(C=O) cm–1. MS: m/z (%)
=
329.8/331.7 (100) [M+H+].
Chromatography [Hex/EtOAc (2:1)]: Rf = 0.43. C15H21ClN2O4
(328.79): calcd. C 54.79, H 6.44, N 8.52; found C 54.57, H 6.59, N
8.52.
Ethyl 3-[7-Methyl-1,3-dioxo-2-propyl-2,3,5,8-tetrahydroimidazo[1,5-
a]pyridin-8a(1H)-yl]propanoate (15h): Yield: 0.16 g (86%). 1H
NMR (300 MHz, CDCl3): δ = 0.93 (t, J = 7.4 Hz, 3 H,
CH2CH2CH3), 1.24 (t, J = 7.2 Hz, 3 H, CH2CH3), 1.66 (sext, J =
7.4 Hz, 2 H, NCH2CH2), 1.74 (s, 3 H, CCH3), 2.05–2.24 (m, 6 H,
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NCH2CH2), 3.51 (dddd, J = 17.9 Hz, J = 12.5 Hz, J = 4.6 Hz, J
= 2.2 Hz, 1 H, NCHAHB), 4.10 (q, J = 7.2 Hz, 2 H, CH2CH3),
4.36 (d, J = 17.9 Hz, 1 H, NCHAHB), 5.44 (s, 1 H, CH) ppm. 13C
NMR (75 MHz, CDCl3): δ = 11.29 (CH3 pr), 14.22 (CH2CH3),
21.60 (CH2 pr), 23.51 (CCH3), 28.55 (COCH2), 28.85
(COCH2CH2), 36.38 (CCH2C), 37.72 (NCH2), 40.42 (NCH2 pr),
60.93 (Cq + CH2CH3), 116.78 (CH), 129.42 (C), 155.24 (NC=ON),
172.48 (HNC=O), 175.81 (C=OO) ppm. 13C NMR (75 MHz,
C6D6): δ = 11.05 (CH3 pr), 13.92 (CH2CH3), 21.60 (CH2 pr), 22.93
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Eur. J. Org. Chem. 2006, 2649–2660
© 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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2659

C. V. Stevens et al.
FULL PAPER
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[37] For clarity only one part of the disorder is shown: O240 is
disordered with a 56:44 ratio.
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Received: January 20, 2006
Published Online: April 3, 2006
2660
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© 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2006, 2649–2660